While hypertension is an important health problem in America affecting over 58 million people, in 90% of cases the cause is unknown. Adrenal steroids are believed to cause hypertension in a small percentage of these. We are proposing two hypothesis: the first addresses an unusual form of primary aldosteronism called Glucocorticoid-Suppressible Aldosteronism (GSA). In these patients """"""""The abnormal secretion of adrenal steroids is due to a persistence of the Transitional zone of the adrenal which replaces the normal Zona Fasciculata"""""""". The transitional zone of the adrenal retains the Cytochrome P-450 methyl oxidase (s) normally present only in the glomerulosa and acquires the 17a-hydroxylase of the fasciculata, resulting in the excessive secretion of the hybrid steroids 18-hydroxycortisol and 18-oxocortisol. We propose to study the regulation of these two steroids using recently developed RIAs to measure their plasma and urine concentrations. We will also measure their secretory and metabolic clearance rates and study the in vivo metabolism of these steroids to determine their main metabolites. We are also postulating that the defect in these patients is due to the absence of an intracellular inhibitor of the late pathway of aldosterone secretion which leads to the persistence of the enzyme in areas of the adrenal where it is not supposed to be active. We have detected such an inhibitor and are proposing to study its regulation, intracellular location and characterization using bovine adrenal zona glomerulosa and fasciculata in culture. The second hypothesis expressed that """"""""The adrenal defect in some cases of essential hypertension is analogous to the adrenal defect which occurs in the Dahl S, or salt sensitive, rat model of hypertension, considering that the human adrenal produces mainly 17a-hydroxylated steroids"""""""". In the human the steroids produced would be 18-hydroxy-11-deoxycortisol (which we have identified) and 19-hydroxy-11-deoxycortisol. We have design methods for their measurement and are proposing to study their plasma and urine concentrations and regulation. It is also postulated that these steroids, rather than producing the hypertension themselves, are markers of more biologically active steroids which we propose to try to identify.
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